KTE-C19 Leads to High Response Rates in Refractory NHL

Sattva S. Neelapu, MD

Almost 80% of patients with treatment-refractory non-Hodgkin lymphoma (NHL) had objective responses following treatment with KTE-C19, a chimeric antigen receptor (CAR) T-cell therapy targeting CD19, according findings from the phase II ZUMA-1 study reported at the 2016 ASH Annual Meeting.

Almost half of the patients achieved complete responses (CR; 52%), which tended to occur rapidly, usually by the first assessment of tumor response. In a subgroup of 62 patients followed for 3 months, 39% still had a CR. The KTE-C19 CAR T-cell therapy demonstrated high-level activity against diffuse B-cell lymphoma (DLBCL), primary mediastinal B-cell lymphoma (PMBCL), and transformed follicular lymphoma (TFL).

Responses, including complete responses, were observed in patients who had progressed after autologous stem-cell transplant (ASCT) and patients whose disease had demonstrated refractoriness to two or more previous lines of therapy.

“This is the first pivotal, multicenter study of anti-CD19 CAR T cells in refractory, aggressive NHL. The trial had a 99% manufacturing success rate associated with a 17-day turnaround time,” said Sattva S. Neelapu, MD, associate professor of lymphoma/myeloma at the University of Texas MD Anderson Cancer Center.

Grade ≥3 adverse events were primarily hematologic, including neutropenia in two-thirds of patients. Cytokine release syndrome and neurologic events of grade ≥3 in severity occurred in 13% and 29% of patients, respectively, but were generally reversible, he said. Three patients died during treatment, including two deaths that were treatment related.

“Adverse event management was effectively implemented across 22 sites, most of which had no prior CAR T-cell therapy experience,” Neelapu noted.

A recent meta-analysis that included 635 patients with refractory DLBCL showed an objective response rate of 26%, CRs in 8%, and median overall survival of 6.6 months, suggesting a very poor prognosis and setting the bar for historical comparisons (ASCO 2016; abstract 7516).

“We observed a sixfold higher complete response rate as compared with historical outcomes (P <.0001), and 39% of responses were durable at 3 months,” said Neelapu.

The need for new, novel, and more effective approaches to treat aggressive, refractory DLBCL provided impetus to develop and evaluate CAR T-cell therapy. The KTE-C19 construct consists of an extracellular domain containing the FMC63 single chain variable fragment, which recognizes and targets the CD19 antigen on the surface of tumor cells, and the intracellular CD28 and C3-zeta domains to avoid activation of hidden signals to the T-cells

KTE-C19 was evaluated in the multicenter phase I/II ZUMA-1 study involving patients with treatment-refractory NHL, including DLBCL, PMBCL, and TFL. The phase I component of the trial demonstrated ongoing complete responses in 43% of patients at 12 months (Mol Ther. 2016 [In Press]).

At the 1-month follow-up, 71% of the patients had achieved objective responses, including CRs in 38% of patients. The overall experience included a 68% response rate in patients with DLBCL and CRs in 33%. The PMBCL/TFL subgroup had an 80% overall response rate, including CRs in 52%.

Among 62 patients followed for at least 3 months, the objective response rate was 79%, and 52% of the patients had CRs. The group comprised 51 patients with DLBCL (76% overall response; 47%, CRs) and 11 with PMBCL/TFL (91% overall response; 73% CRs). Neelapu said CAR T-cell expansion was associated with both ongoing CRs (P = .004) and occurrence of neurologic events (P = .02).

The treatment effect remained consistent across key covariate groups: disease stage, risk score, CD19 H-score, CD4/CD8 ratio, steroid use, and exposure to tocilizumab.

The most frequent treatment emergent grade ≥3 adverse events were neutropenia (63%), anemia (42%), leukopenia (40%), febrile neutropenia (29%), thrombocytopenia (26%), encephalopathy (19%), hypophosphatemia (17%), and decreased lymphocyte count (17%).

Based on findings from the ZUMA-1 trial, Kite Pharma, the company developing the therapy, initiated a rolling FDA submission for the therapy as a treatmen for patients with relapsed/refractory aggressive B-cell NHL who are ineligible for ASCT. The rolling submission of data, which is allowed under a breakthrough therapy designation received by the therapy in December 2015, is expected to complete by the end of the first quarter of 2017.

Neelapu SS, Locke FL, Bartlett NL, et al. KTE-C19 (anti-CD19 CAR T Cells) Induces Complete Remissions in Patients with Refractory Diffuse Large B-Cell Lymphoma (DLBCL): Results from the Pivotal Phase 2 ZUMA-1. Presented at: American Society of Hematology 58th Annual Meeting; December 3-6, 2016; San Diego, CA. Abstract LBA6.

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Phase II of ZUMA-1 included 93 patients: 73 with refractory DLBCL and 21 with refractory PMBCL or TFL. All of the patients had documented chemotherapy-refractory disease, defined as no response to last chemotherapy or relapse within 12 months after ASCT. They had received a median of 3 prior lines of therapy, and some had received as many as 12 regimens.